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Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects over 6 million people worldwide. Development of new drugs to treat this disease remains a priority since those currently available have variable efficacy and frequent adverse effects, especially during the long regimens...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828178/ https://www.ncbi.nlm.nih.gov/pubmed/33445756 http://dx.doi.org/10.3390/ijms22020688 |
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author | Martinez-Peinado, Nieves Martori, Clara Cortes-Serra, Nuria Sherman, Julian Rodriguez, Ana Gascon, Joaquim Alberola, Jordi Pinazo, Maria-Jesus Rodriguez-Cortes, Alheli Alonso-Padilla, Julio |
author_facet | Martinez-Peinado, Nieves Martori, Clara Cortes-Serra, Nuria Sherman, Julian Rodriguez, Ana Gascon, Joaquim Alberola, Jordi Pinazo, Maria-Jesus Rodriguez-Cortes, Alheli Alonso-Padilla, Julio |
author_sort | Martinez-Peinado, Nieves |
collection | PubMed |
description | Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects over 6 million people worldwide. Development of new drugs to treat this disease remains a priority since those currently available have variable efficacy and frequent adverse effects, especially during the long regimens required for treating the chronic stage of the disease. T. cruzi modulates the host cell-metabolism to accommodate the cell cytosol into a favorable growth environment and acquire nutrients for its multiplication. In this study we evaluated the specific anti-T. cruzi activity of nine bio-energetic modulator compounds. Notably, we identified that 17-DMAG, which targets the ATP-binding site of heat shock protein 90 (Hsp90), has a very high (sub-micromolar range) selective inhibition of the parasite growth. This inhibitory effect was also highly potent (IC(50) = 0.27 μmol L(−1)) against the amastigote intracellular replicative stage of the parasite. Moreover, molecular docking results suggest that 17-DMAG may bind T. cruzi Hsp90 homologue Hsp83 with good affinity. Evaluation in a mouse model of chronic T. cruzi infection did not show parasite growth inhibition, highlighting the difficulties encountered when going from in vitro assays onto preclinical drug developmental stages. |
format | Online Article Text |
id | pubmed-7828178 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-78281782021-01-25 Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds Martinez-Peinado, Nieves Martori, Clara Cortes-Serra, Nuria Sherman, Julian Rodriguez, Ana Gascon, Joaquim Alberola, Jordi Pinazo, Maria-Jesus Rodriguez-Cortes, Alheli Alonso-Padilla, Julio Int J Mol Sci Article Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects over 6 million people worldwide. Development of new drugs to treat this disease remains a priority since those currently available have variable efficacy and frequent adverse effects, especially during the long regimens required for treating the chronic stage of the disease. T. cruzi modulates the host cell-metabolism to accommodate the cell cytosol into a favorable growth environment and acquire nutrients for its multiplication. In this study we evaluated the specific anti-T. cruzi activity of nine bio-energetic modulator compounds. Notably, we identified that 17-DMAG, which targets the ATP-binding site of heat shock protein 90 (Hsp90), has a very high (sub-micromolar range) selective inhibition of the parasite growth. This inhibitory effect was also highly potent (IC(50) = 0.27 μmol L(−1)) against the amastigote intracellular replicative stage of the parasite. Moreover, molecular docking results suggest that 17-DMAG may bind T. cruzi Hsp90 homologue Hsp83 with good affinity. Evaluation in a mouse model of chronic T. cruzi infection did not show parasite growth inhibition, highlighting the difficulties encountered when going from in vitro assays onto preclinical drug developmental stages. MDPI 2021-01-12 /pmc/articles/PMC7828178/ /pubmed/33445756 http://dx.doi.org/10.3390/ijms22020688 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Martinez-Peinado, Nieves Martori, Clara Cortes-Serra, Nuria Sherman, Julian Rodriguez, Ana Gascon, Joaquim Alberola, Jordi Pinazo, Maria-Jesus Rodriguez-Cortes, Alheli Alonso-Padilla, Julio Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds |
title | Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds |
title_full | Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds |
title_fullStr | Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds |
title_full_unstemmed | Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds |
title_short | Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds |
title_sort | anti-trypanosoma cruzi activity of metabolism modifier compounds |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828178/ https://www.ncbi.nlm.nih.gov/pubmed/33445756 http://dx.doi.org/10.3390/ijms22020688 |
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